FK506 increases susceptibility to musculoskeletal infection in a rodent model

Abstract

Background

Delayed fracture healing caused by soft tissue loss can be resolved by the administration of a Th1 immunosuppressant, such as FK506. Additionally, open fractures are at high risk for infection. We hypothesized that the inclusion of an immunosuppressant to a subject at risk for a musculoskeletal infection will increase the likelihood of infection.

Methods

A rat model of musculoskeletal infection was used. Sprague Dawley rats received a stabilized femur defect and were inoculated with 10⁴ CFU Staphylococcus aureus via a collagen matrix. Six hours after inoculation, the wounds were debrided of collagen and devitalized tissue and irrigated with sterile saline. The animals were randomized into two groups: carrier control and FK506, which were administered daily for 14 days and were euthanized and the tissues harvested to measure local bioburden.

Results

The dosing regimen of FK506 that restored bone healing increased the bioburden in the bone and on the fixation implant compared to the carrier control animals. As expected, the administration of FK506 decreased circulating white blood cells, lymphocytes, neutrophils, and monocytes. Additionally, the red blood cell count, hematocrit, and body weight were lower in those animals that received FK506 compared to carrier control.

Conclusions

FK506 administration decreased the systemic immune cell counts and increased the bacterial bioburden within a model of musculoskeletal infection. Collectively, these outcomes could be attributed to the overall T cell suppression by FK506 and the altered antimicrobial activity of innate cells, thereby allowing S. aureus to thrive and subsequently leading to infection of severe, musculoskeletal injuries. These observations reveal the crucial continued investigation for the clinical use of FK506, and other immunosuppressant compounds, in trauma patients who are at increased risk of developing infections.